Angiotensin (Ang) II are known to mediate the progression of chronic kidney disease (CKD) and cardiac disease. Hence, angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) have been used extensively to treat these clinical disorders. However, these agents often do not halt the disease processes. A potential reason for this limitation in success is the increase in prorenin and renin production, as a result of positive feedback. Renin and its precursor prorenin are biological active molecules, independent of the proteolytic action of renin that leads to the subsequent generation of Ang II. This Ang-independent pathway is initiated by the binding of either prorenin or renin to the (pro)renin receptor, that is present in the kidney, heart and eye. This receptor binding leads to the activation of intracellular signaling proteins that results in pro-proliferatie and pro-fibrotic cellular events that are not blocked by clinically used ACEI, ARB or direct renin inhibitors. Several small clinical studies have found a correlation between serum prorenin/renin levels with the development of microvascular diseases, including albuminuria and retinopathy, in patients with diabetes. Animal studies also found that activation of the (pro)renin receptor induces cardiac diseases. The over-arching hypothesis of the present proposal is that binding of prorenin and renin to the cellular (pro)renin receptor causes organ damage in an Ang-independent manner. Therefore, high serum levels of prorenin and/or renin are associated with CKD progression as well as the development or progression of heart failure and retinopathy. The NIDDK-sponsored Chronic Renal Insufficiency Cohort (CRIC) has enrolled 3,939 people with CKD in a longitudinal observational study. A variety of clinical and laboratory data as well as biospecimens have been collected during a 10-year follow-up period. This parent CRIC Study therefore provides an ideal setting to test our hypotheses. Prorenin and renin will be measured using highly specific immunoassays in archived serum samples collected annually from CRIC participants. Using these assay results, we propose to: (i) characterize the distribution of serum prorenin and renin levels and their longitudinal variations; (ii) determine te association of serum prorenin and renin levels with subsequent CKD progression; (iii) determine the association of serum prorenin and renin levels with subsequent changes in cardiac function on echocardiography and clinical cardiac events; and (iv) determine the cross-sectional association of serum prorenin and renin levels with retinopathy on fundoscopic examination. The proposed study will develop novel insights into the pathogenic roles of prorenin and renin. Importantly, positive results will provide strong rationales to develop new strategies to target th Ang II-independent effects of prorenin and renin for the treatment of nephropathy, retinopathy and cardiac failure. This project perfectly aligns with the mission of the NIDDK to study and develop treatments for people with CKD and diabetes.